Efficacy and safety of saroglitazar for the management of dyslipidemia: A systematic review and meta-analysis of interventional studies

Background and objective Saroglitazar is a newer antidiabetic agent approved to manage dyslipidemia. The objective is tevaluate the efficacy and safety profiles of saroglitazar in patients with dyslipidemia. Methods A systematic search was conducted using PubMed, Cochrane Library, Scopus, and Google Scholar from the inception until January 2022. Interventional studies comparing the anti-hyperlipidaemic effect and safety of saroglitazar with or without a control group(s) were included. The efficacy of saroglitazar was assessed concerning its effect on total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL)-cholesterol, triglycerides, fasting plasma glucose, and non-HDL cholesterol. The effects on serum creatinine levels, bodyweight reduction, alanine aminotransferase and aspartate aminotransferase were considered to be safety endpoint.The Cochrane risk of bias assessment tool was used to assess the methodological quality of the included studies. Results A total of six studies with 581 adults with a mean age ranging from 40.2 to 62.6 years were included in this study. A significant decrease in low-density lipoprotein cholesterol was observed with saroglitazar 4 mg therapy compared to saroglitazar 2 mg [standardized mean difference (SMD): −0.23 mg/dL, 95% CI: −0.47 to 0.00; p  =  0.05; 2 studies], and control [SMD: −0.36 mg/dL, 95% CI −0.59 to -0.12; p  =  0.0026; 3 studies]. Also, a significant decrease in the total cholesterol was observed with saroglitazar 4 mg therapy compared to saroglitazar 2 mg [SMD − 0.28 mg/dL, 95% CI: − 0.52 to -0.04; p < 0.01; 2 studies], and control [SMD − 0.49 mg/dL, 95% CI: − 0.72 to -0.26; p < 0.0001; 3 studies]. Saroglitazar was not associated with adverse effects such as increase in serum creatinine levels, alanine aminotransferase and aspartate aminotransferase and bodyweight reduction. Conclusion Saroglitazar appeared to be an effective and safer therapeutic option for improving dyslipidemia in patients. However, comparative studies of saroglitazar with the other pharmacological agents are warranted.


Introduction
According to the atlas of the International Diabetes Federation (IDF), globally, 463 million individuals have diabetes, and it is expected to reach up to 578 million by 2030 and 700 million by 2045 [1]. In India, around 77 million individuals live with type-2 diabetes (T2D) as of 2019, and >4 million people aged between 20-79 years have died from diabetes-related causes [1]. Cardiovascular diseases (CVD) are the primary cause of morbidity and mortality among individuals with T2D [2], where cardiovascular risk tends to be primarily influenced by dyslipidemia [3]. The anti-hyperlipidaemic agents have been studied for decades, and evidence supports their cardiovascular benefit in selected patients with the presence or absence of T2D [4]. Diabetic dyslipidemia is a type of lipoprotein dysfunction characterized by decreased high-density lipoprotein levels, an increase in triglyceride levels, and an increase in low-density lipoprotein (LDL) particles [5]. Approximately around 70% of the patients who have T2D are likely to develop dyslipidemia [6].
Statins, fibrates, cholesterol absorption inhibitors, niacin, bile acid sequestrants, proprotein convertase subtilisin/kexin type-9 (PCSK-9) inhibitors are the available therapeutic options to treat dyslipidemia [5]. However, the use of statins and fibrates is associated with myopathy [7], where niacin is usually not recommended due to the risk of new-onset of diabetes [8], bleeding, and infections [9], and PCSK-9 inhibitors are more expensive and cause injection site reactions. Hence, there is an immense need for newer medications that can potentially target both dyslipidemias as well as T2D [10]. In patients with T2D, peroxisome proliferator-activated receptor alpha (PPAR-α) agonist improves lipid profile, whereas PPAR-γ agonist improves glucose profile [11].
Dual PPAR α/γ agonists have multiple actions, where they act by improving both lipids as well as glucose profiles [12,13]. Saroglitazar [(S)-a-ethoxy-4-{2-[2-methyl-5-(4-methylthio) phenyl)]-1H-pyrrol-1-yl]-ethoxy)-benzenepropanoic acid magnesium salt] is a novel PPAR α/γ agonist synthesized in India by Zydus Cadila (trade name, Lipaglycn), and is approved by the Drug Controller General of India (DCGI) for the treatment of diabetic dyslipidemia and hypertriglyceridemia [14]. Saroglitazar is not associated with weight gain and edema [13], and thus it is considered a safer medication, with fewer adverse effects such as gastritis, asthenia, and pyrexia [15]. There is a lack of pooled evidence on the safety and efficacy of saroglitazar for the treatment of dyslipidemia. With this background, we conducted a systematic review and meta-analysis aimed to examine the efficacy and safety of saroglitazar for managing dyslipidemia.

Methods
The current systematic literature review was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16].

Eligibility criteria for included studies
The research question for our systematic review is "What is the safety and efficacy of saroglitazar for the management of hypercholesterolemia?" The research question was broken down into PICOS (population, intervention, comparison, outcome, and study design) format. Population (P) comprises adult patients with hypercholesterolemia with or without diabetes. Intervention (I) consists of saroglitazar in any of its effective doses. Comparator (C) was any comparator such as different doses, control, or another drug as per the author's discretion. Outcomes (O) considered were efficacy and safety of Saroglitazar. The effect of saroglitazar on total cholesterol, LDL-cholesterol, triglycerides, high-density lipoprotein (HDL)-cholesterol, non-HDL cholesterol, and fasting plasma glucose is considered to be efficacy outcomes. While the reduction in Serum Creatinine, Alanine Transaminases, Aspartate Transaminases, and body weight considered to be safety outcomes. In study design (S), we included all types of interventional studies; randomized, and non-randomized trials. Any studies satisfying the above specified PICOS were included in the systematic review. Reviews, observational and descriptive studies, editorials, commentaries, and conference proceedings were excluded.

Data sources and literature search
A comprehensive literature search was performed using PubMed, Scopus, the Cochrane Library, and Google Scholar from the inception to January 2022. The initial search was performed in April 2019 and was updated in January 2022. We employed all the MesH terms and keywords related to "Saroglitazar" and "hypercholesterolemia" obtained from the databases and previously published studies. In addition to this, all the references of the included studies and a snowball search through Google were performed to search for any additional relevant articles. A detailed search strategy for each database is provided in S1 File.

Study selection and data extraction
The titles and abstracts of retrieved studies were screened, followed by the full text under the predefined inclusion and exclusion criteria. The highly irrelevant studies only were excluded during the title/abstract screening. Two independent reviewers performed the title and abstract screening, followed by full-text screening. A well-defined data extraction sheet was employed for the data abstraction, including the information about studies' characteristics, participants, interventions, comparator, and outcomes. Two independent researchers were involved in study selection and data extraction, disagreements were resolved through consensus or by a discussion with a third reviewer.
of included studies and resolved any disagreements through consensus or by a discussion with a third reviewer.

Data synthesis
The analyses were performed with R software (R version 4.1.2) using a meta-package. Changes in continuous outcomes were calculated for every included study arm by subtracting the value at baseline from the value after the intervention. All the efficacy estimates were expressed as standardized mean difference (SMD) or absolute weighted mean change (MRAW) and 95% confidence interval (CI) from baseline. According to the Cochrane handbook, standard deviations (SD) were calculated from the standard error or 95% CI for a systematic review of interventions [17]. The Higgins I2 statistics and Cochran's Q test were used to assess the potential statistical heterogeneity among trials. The meta-analysis was conducted using a fixed-effect model (using inverse-variance) or a random-effect model (DerSimonian-Laird method) based on low heterogeneity (<50%) or high heterogeneity (>50%). Due to less number of included studies (<10), it was not feasible to examine the publication bias through a funnel plot, Egger's and Begg's test [17].

Results
A total of 272 citations were identified by electronic search of databases, and 18 citations were identified through hand search. Finally, 276 citations were screened after removing 14 duplicates, while 250 studies were excluded during first-pass screening after reviewing the titles and abstracts. Full texts of 26 citations included during the first pass screening were downloaded for the second pass screening. Lastly, 6 articles met our inclusion criteria. PRISMA flowchart for the study selection is described in Fig 1.

Treatment and outcome characteristsics
There was a total of 581 participants from six studies, of whom the majority of them were females (302 [52%]). All the studies have included adult participants with a mean age of 40.2 [20] to 62.6 years [22]. Of six included studies, two studies [12,19] have compared the effect of saroglitazar 4mg to saroglitazar 2mg and control. The details about treatment and outcome characteristics of included studies are presented in Table 2.

Quality assessment
Risk of bias of the included studies was assessed using the Cochrane risk of bias assessment tool. Bias related to randomization was low among three (75%) studies, while it appeared to have a higher level of bias with the remaining one study. Bias related to the allocation concealment was found to be low (n = 3; 75%) and moderate (n = 1; 25%) among the studies, respectively. Information about blinding participants and assessors was mentioned in three studies. As per the NIH checklist, both Bhosle D et al., 2018 and Deshpande A et al., 2016 trials did not report the information related to the masking of patients or investigators and did not report the sufficient details of the group-level interventions and individual-level outcome efforts. But overall, two trials were rated as good quality as per rating of NIH checklist. Detailed information on overall risk of bias in individual studies is provided in in Figs 2 and 3 and S1 Table. Efficacy of saroglitazar Total cholesterol. Two studies [12,19] compared the saroglitazar 4 mg with 2 mg per day, where there were 138 patients each in the saroglitazar 4 mg/day and 2 mg/day groups that

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resulted in a standardized absolute mean difference (SMD) of -0.28 mg/dL, on total cholesterol (95% CI -0.52 to -0.04), p = 0.01 (Fig 4). This demonstrates a significant decrease in the total cholesterol among the saroglitazar 4 mg/day group compared to saroglitazar 2 mg/day group in patients with diabetes-related hyperlipidaemia (Table 3). There was no statistically significant heterogeneity among included studies (P = 0.29; I 2 = 12%). Besides, three studies [12,18,19] compared the saroglitazar 4 mg with control, where there were 148 patients in saroglitazar 4 mg/day group and 144 patients in the control group. The results showed an SMD of -0.49 mg/dL, (95% CI -0.72 to -0.26), P<0.0001 (Fig 5). This demonstrates a significant decrease in the total cholesterol among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.42; I 2 = 0%). LDL-cholesterol. The pooled analysis of two studies [12,19] compared the saroglitazar 4 mg with saroglitazar 2mg, where 138 patients in each group resulted in an SMD of -0.24 mg/ dL, (95% CI -0.47 to 0.00), P = 0.05 (Fig 6). This demonstrates a significant decrease in the LDL cholesterol among the Saroglitazar 4 mg/day group compared to saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). There was no statistically significant heterogeneity among included studies (p = 0.44; I 2 = 0%). At the same time, three studies compared the saroglitazar 4 mg with control, where there were 148 patients in the saroglitazar 4 mg/day group and 144 patients in the control group [12,18,19]. The results showed an SMD of -0.36 mg/dL, (95% CI -0.59 to -0.12), p = 0.0026 (Fig 7). This demonstrates a significant decrease in the LDL cholesterol among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was detected among included studies (P<0.83; I 2 = 0%).
Triglycerides. The pooled analysis of two studies [12,19] compared the saroglitazar 4 mg with Saroglitazar 2mg, where there were 138 patients in each group, resulting in an SMD of -0.24 mg/dL, (95% CI -0.64 to 0.15), P = 0.22 (Table 3). There was no statistically significant heterogeneity among included studies (P = 0.13; I 2 = 55%). This demonstrates a non-significant decrease in the triglycerides among the saroglitazar 4 mg/day group compared to the saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). Besides, four studies compared the saroglitazar 4 mg with control, where there were 167 patients in the saroglitazar 4 mg/day group and 162 patients in the control group [12,18,19,23]. The results showed an SMD of -0.28 mg/dL, (95% CI -0.84 to 0.27), P = 0.31 (Table 3). This demonstrates a decrease in the triglycerides among the saroglitazar 4 mg/day group compared to the control group in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P<0.01; I 2 = 78%).
HDL-cholesterol. The pooled analysis of two studies [12,19] compared the saroglitazar 4 mg with Saroglitazar 2mg, where there were 138 patients in each group. The results showed an SMD of -0.17 mg/dL, (95% CI -0.41 to 0.07), P = 0.15 (Table 3). This demonstrates a non-significant decrease in the HDL-cholesterol among the Saroglitazar 4 mg/day group compared to the saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). No

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Saroglitazar for dyslipidemia: A meta-analysis statistically significant heterogeneity was observed among included studies (P = 0.62; I 2 = 0%). Besides, three studies [12,18,19] compared the saroglitazar 4 mg/day with control, where there were 148 patients in saroglitazar 4 mg/day group and 144 patients in the control group. The results showed an SMD of 0.24 mg/dL, (95% CI -0.29 to 0.76), P = 0.37 (Table 3). This demonstrates a non-significant decrease in the HDL-cholesterol among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). Statistically, significant heterogeneity was observed among included studies (P = 0.04; I 2 = 70%).
Fasting plasma glucose. Two studies [12,19] compared the saroglitazar 4 mg with Saroglitazar 2mg, where there were 138 patients in each group. The results showed an SMD of -0.07

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Saroglitazar for dyslipidemia: A meta-analysis mg/dL, (95% CI -0.30 to 0.17), P = 0.56 (Table 3). This demonstrates a non-significant decrease in the fasting plasma glucose among the saroglitazar 4 mg/day group compared to Saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). No
Besides, four studies [12,18,19,22] compared the saroglitazar 4 mg with control, where there were 167 patients in saroglitazar 4 mg/day group and 162 patients in the control group. The results showed an SMD of -0.22 mg/dL, (95% CI -1.38 to 0.94), P = 0.71 (Table 3). This demonstrates a non-significant decrease in the fasting plasma glucose among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). Statistically, significant heterogeneity was observed among included studies (P = 0.01; I 2 = 94%). Non-HDL cholesterol. Three studies [18,19,22] compared the saroglitazar 4 mg/day with control, where there were 68 patients in the saroglitazar 4 mg/day group and 60 patients in the control group. The results showed a SMD of -0.66 mg/dL, (95% CI -1.77 to 0.45), P = 0.24 (Table 3). It demonstrates a non-significant decrease in the non-HDL cholesterol among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). Statistically, significant heterogeneity was observed among included studies (P<0.01; I 2 = 87%).

Safety of saroglitazar
Serum creatinine levels. Two studies [12,19] compared the saroglitazar 4 mg with the saroglitazar 2mg, where there were 132 patients in the saroglitazar 4 mg/day group, and 138 patients in the saroglitazar 2 mg/day group. The meta-analysis demonstrated a significant increase (SMD: 0.45 mg/dL; 95% CI 0.21 to 0.69; P = 0.0003) [Fig 8] in the serum creatinine levels among the saroglitazar 4 mg/day group compared to the saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.41; I 2 = 0%). Besides, two studies [12,19] compared the saroglitazar 4 mg with control, where there were 132 patients in the saroglitazar 4  (Table 3). It demonstrates a non-significant increase in the serum creatinine levels among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). Statistically significant heterogeneity was observed among included studies (P<0.01; I 2 = 92%).

Bodyweight reduction
Two studies [12,19] compared the saroglitazar 4 mg with saroglitazar 2mg, where there were 132 patients in saroglitazar 4 mg/day group and 138 patients in Saroglitazar 2 mg/day group. The results showed an SMD of 0.27 kg, (95% CI 0.03 to 0.51), P = 0.02 (Table 3). It demonstrates a significant increase in the bodyweight reduction among the saroglitazar 4 mg/day group compared to the saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.61; I 2 = 0%). Besides, two studies [12,19] compared the saroglitazar 4 mg with control, where there were 132 patients in the saroglitazar 4 mg/day group and 139 patients in the control group. The results showed an SMD of -0.09 kg, (95% CI -0.92 to 0.73), P = 0.82 (Table 3). It demonstrates a non-significant decrease in the bodyweight reduction among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). Statistically, significant heterogeneity was observed among included studies (P<0.01; I 2 = 89%).

Alanine aminotransferase
Two studies [12,19] compared the saroglitazar 4 mg with saroglitazar 2mg, where there were 132 patients in Saroglitazar 4 mg/day group and 138 patients in saroglitazar 2 mg/day group.

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The results showed an SMD of -0.07 U/L, (95% CI -0.31 to 0.17), P = 0.56 (Table 3) which demonstrates a non-significant decrease in the alanine aminotransferase among the Saroglitazar 4 mg/day group compared to the saroglitazar 2 mg/day group in patients with diabetesrelated dyslipidemia (Table 3). There was no statistically significant heterogeneity among included studies (P = 0.28; I 2 = 15%). Besides, two studies [12,19] compared the saroglitazar 4 mg with control, where there were 132 patients in the saroglitazar 4 mg/day group and 139 patients in the control group. The results showed an SMD of -0.17 U/L, (95% CI -0.41 to 0.07), P = 0.16 (Table 3). This demonstrates a non-significant decrease in the alanine aminotransferase among the saroglitazar 4 mg/day group compared to the control in patients with diabetesrelated dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.41; I 2 = 0%).

Aspartate aminotransferase
Two studies [12,19] compared the saroglitazar 4 mg with saroglitazar 2mg, where there were 132 patients in the saroglitazar 4 mg/day group and 138 patients in Saroglitazar 2 mg/day group. The results showed an SMD of -0.06 U/L, (95% CI -0.30 to 0.18), P = 0.64 (Table 3). This demonstrates a non-significant decrease in the aspartate aminotransferase among the saroglitazar 4 mg/day group compared to saroglitazar 2 mg/day group in patients with diabetesrelated dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.55; I 2 = 0%). Besides, two studies [12,19] compared the Saroglitazar 4 mg with control, where there were 132 patients in Saroglitazar 4 mg/day group and 139 patients in the control group. The results showed an SMD of -0.05 U/L, (95% CI -0.19 to 0.29), P = 0.68 (Table 3). This demonstrates a non-significant decrease in the aspartate aminotransferase among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.318; I 2 = 0%). The summary of all clinical outcomes are presented in Table 3.

Discussion
The current systematic review and meta-analysis looked at the efficacy and safety of Saroglitazar among patients with diabetic dyslipidemia with or without diabetes. This study is the first of its kind that attempted to summarise the efficacy and safety profiles of Saroglitazar; the overall results of this study are encouraging with a reduction in fasting plasma glucose, triglycerides, total cholesterol, LDL-cholesterol, serum creatinine, and body weight, along with improved safety outcomes including hepatotoxicity and renal toxicity.
Diabetic dyslipidemia is a condition that is characterized by low concentrations of HDL with elevated triglycerides, LDL, and postprandial lipemia [24]. At the same time, hypertriglyceridemia is also a notable risk factor and is present in almost 50% of the patients with type-2 diabetes, which is often unresponsive to statins [25]. Since higher levels of triglycerides could significantly increase the risk of cardiovascular diseases, triglycerides management has become the chief priority, especially in patients with diabetes [26]. saroglitazar is a dual peroxisome proliferator-activated receptor (PPAR) agonist with predominant PPAR-α and moderate -γ agonism that can optimise both lipid and glycaemic levels.
Among patients with diabetic dyslipidemia who were not responded to the atorvastatin therapy, a phase III study of saroglitazar has shown a significant improvement in triglyceride, LDL cholesterol, non-HDL-C VLDL, total cholesterol, and fasting plasma glucose [12]. The findings of another phase III clinical trial inferred that saroglitazar could be an alternative for patients those experience the common side effects of fibrates and pioglitazone. However, there is a further need for studies of saroglitazar to well-establish its role in the management of diabetes with dyslipidemia [27]. Furthermore, alongside the favourable finding from the existing clinical trials [12,[18][19][20][21][22], the results of a post-marketing study had demonstrated a significant reduction in the triglycerides (35.8%), non-HDL-C (23.4%), LDL-C (16.4%), and total cholesterol (19%) including HbA1c, FBG and PPBG levels with the saroglitazar 4 mg in patients with diabetic dyslipidemia [28].
In addition, 4 mg saroglitazar has shown the potentiality in decreasing glycaemic-related outcome measures such as FPG to a significant extent (SMD of -0.22 and -0.07) when compared to the control and 2 mg saroglitazar [19,21], which might be a result of its PPAR-c agonist activity. As a result, saroglitazar is emerging as a first-line choice for diabetic dyslipidemia with hypertriglyceridemia for its both lipid and glucose-lowering effects. Safety analysis of saroglitazar revealed no serious adverse events, including hepatotoxicity and renal toxicity in any of the clinical trials, which might be due to its non-renal route of excretion. [29] Instead, it showed a reduction in the ALT (absolute weighted mean difference of 13.6), AST (13.9) and serum creatinine levels for saroglitazar 2mg (0.51) [19,21]. All the reported adverse events like dyspepsia, gastritis, pyrexia were mild in severity and ranged from 10% to 17%, which seems to be better compared to the control groups (up to 20%) [19,20].
Besides exhibiting improved outcomes among patients with diabetes, saroglitazar also showed a significant reduction in serum triglyceride and VLDL levels and increased HDL levels in patients with HIV-associated lipodystrophy [20]. Among patients who are unresponsive or contra-indicated to fibrates and statin therapies, saroglitazar has the potential to undertake the cardiovascular risk associated with high triglyceridemia [19]. Also, since saroglitazar has both antidyslipidemic and anti glycemicglycaemic actions, it would have the ability to address the uncertainties in the reduction of macrovascular and microvascular complications. However, as most of these studies are clinical trials with shorter durations, findings on more extensive observational studies using real-world evidence are warranted.

Limitations
There are certain limitations associated with this study that must be considered while interpreting the findings. Firstly, all the studies included in this systematic review and meta-analysis were clinical trials, which usually account for a limited sample size with a minimum duration of the follow-up period, which makes it difficult to assess the long-term safety and efficacy of saroglitazar. Secondly, some of these studies were single-center and single-arm trials without a comparator group. Thirdly, these findings could not be generalizable to all the patients with dyslipidemia, as all the included studies were solely conducted in India. In addition to this, all the included trials had shorter follow-up duration with surrogate outcomes.

Conclusions
The current evidences, suggests saroglitazar to be effective in reducing LDL cholesterol, non-HDL-C, triglycerides, total cholesterol, and fasting plasma glucose among the dyslipidemic patients. Furthermore, it is appeared to be safe in terms of liver enzymes abnormality and body weight. However, studies are needed to compare the effect of saroglitazar with other antihyperlipidemic medications.